Liver, which plays a major role in regulating bodily metabolic functions, is often the target of systemic insults arising from endotoxins, xenobiotics etc., resulting in hepatic injury. Recent studies have shown that hepatic injury is closely linked to the way Kupffer cells react to such insults and that obliteration of Kupffer cells can prevent liver injury. The Kupffer cell-mediated liver injury has been attributed to the excessive release of cytokines like tumor necrosis factor-alpha, interleuken-1, IL-6 and prostanoids, during endotoxemia. Endotoxins have been implicated in alcoholic liver diseases, since, high levels of endotoxins have been reported in the blood of alcoholic patients with liver disease. The objective of this proposal therefore, is to develop a method by which to control the production of cytokines and prostanoids in Kupffer cells. To achieve this goal, a method will be developed in which antisense and/antigene molecules, which are specifically targetted to the inflammatory cytokine/prostanoid-gene products will be encapsulated in anionic liposomes and delivered in vivo to Kupffer cells. The efficacy of delivery will be assessed by monitoring a) the tissue distribution of the delivered molecule, b) its biological half-life and c) cellular levels of targetted mRNA. Based on other reports, during the final year of the fellowship period, the molecular species of the liposomes will be modified to target other cell types such as hepatocytes and splenic macrophages. Positive data from such exploratory experiments will set the stage for future investigations with wider scope.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32AA005529-02
Application #
6127126
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (01))
Project Start
1999-08-01
Project End
Budget Start
1999-08-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305